TY - JOUR
T1 - Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2)
T2 - a prospective, randomised, double-blind, placebo-controlled study
AU - Hacke, Werner
AU - Furlan, Anthony J.
AU - Al-Rawi, Yasir
AU - Davalos, Antoni
AU - Fiebach, Jochen B.
AU - Gruber, Franz
AU - Kaste, Markku
AU - Lipka, Leslie J.
AU - Pedraza, Salvador
AU - Ringleb, Peter A.
AU - Rowley, Howard A.
AU - Schneider, Dietmar
AU - Schwamm, Lee H.
AU - Leal, Joaquin Serena
AU - Söhngen, Mariola
AU - Teal, Phil A.
AU - Wilhelm-Ogunbiyi, Karin
AU - Wintermark, Max
AU - Warach, Steven
N1 - Funding Information:
WH was a consultant and advisory board member for Paion and has received honoraria for being the chairman of the steering committee from Forest, Paion, and Lundbeck. AJF has been a consultant for Forest and Paion, and a North American principal investigator for the DEDAS and DIAS-2 studies. YA was an employee of Paion Deutschland GmbH at the time of and analysis of the study. AD received fees as a consultant, paid speaker, or advisory board member from Ferrer Grupo, Paion, Lundbeck, Boehringer Ingelheim, Pfizer, and BMS. JBF has served as a consultant and received honoraria and lecture fees from Forest and Paion. MK has received honoraria for attending the DIAS-2 steering committee meetings from Forest. LJL is an employee of Forest Laboratories. SP has served as a consultant to Paion and a member of the DIAS-2 imaging committee. PAR has received speaker fees from and consulted for Paion. HAR has been a consultant for Forest and Paion, and has received fees as consultant for research agreements with GE Healthcare, Bracco, BTG, and Nuvelo. LHS has served as a consultant for Coaxia, the Research Triangle Institute, and the Massachusetts Department of Public Health, and has occasionally served as an expert reviewer of malpractice cases related to cerebrovascular disease. MS is an employee of Paion Deutschland GmbH, a member of the management board of Paion AG, and a shareholder in the company. PAT has received an honorarium for services on the DIAS-2 steering committee. KWO is an employee of Paion Deutschland GmbH and owns stock options in Paion. MW receives funding from the National Center for Research Resources, Grant KL2 RR024130, GE Healthcare, Philips Medical Systems, and Boston Scientific, and was a consultant for Paion, Lundbeck, and Concentric at the time of the study. FG, DS, JSL, and SW have no conflicts of interests.
PY - 2009/2
Y1 - 2009/2
N2 - Background: Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI). Methods: In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (1:1:1) to 90 μg/kg desmoteplase, 125 μg/kg desmoteplase, or placebo within 3-9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0-2 points, and a Barthel index of 75-100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00111852. Findings: Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 μg/kg desmoteplase; 66 received 125 μg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6-14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10·6 cm3 and 52·5 cm3, respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 μg/kg desmoteplase, 36% (24 of 66) for 125 μg/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 μg/kg desmoteplase 14·0% (0·5 cm3); 125 μg/kg desmoteplase 10·8% (0·3 cm3); placebo -10·0% (-0·9 cm3). The rates of symptomatic intracranial haemorrhage were 3·5% (2 of 57) for 90 μg/kg desmoteplase, 4·5% (3 of 66) for 125 μg/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 μg/kg desmoteplase; 21% [14 of 66] for 125 μg/kg desmoteplase; and 6% [4 of 63] for placebo). Interpretation: The DIAS-2 study did not show a benefit of desmoteplase given 3-9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase. Funding: PAION Deutschland GmbH; Forest Laboratories.
AB - Background: Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI). Methods: In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (1:1:1) to 90 μg/kg desmoteplase, 125 μg/kg desmoteplase, or placebo within 3-9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0-2 points, and a Barthel index of 75-100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00111852. Findings: Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 μg/kg desmoteplase; 66 received 125 μg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6-14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10·6 cm3 and 52·5 cm3, respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 μg/kg desmoteplase, 36% (24 of 66) for 125 μg/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 μg/kg desmoteplase 14·0% (0·5 cm3); 125 μg/kg desmoteplase 10·8% (0·3 cm3); placebo -10·0% (-0·9 cm3). The rates of symptomatic intracranial haemorrhage were 3·5% (2 of 57) for 90 μg/kg desmoteplase, 4·5% (3 of 66) for 125 μg/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 μg/kg desmoteplase; 21% [14 of 66] for 125 μg/kg desmoteplase; and 6% [4 of 63] for placebo). Interpretation: The DIAS-2 study did not show a benefit of desmoteplase given 3-9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase. Funding: PAION Deutschland GmbH; Forest Laboratories.
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U2 - 10.1016/S1474-4422(08)70267-9
DO - 10.1016/S1474-4422(08)70267-9
M3 - Article
C2 - 19097942
AN - SCOPUS:58249134578
SN - 1474-4422
VL - 8
SP - 141
EP - 150
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 2
ER -